Brain rescue instrument and method

ABSTRACT

An intelligent brain rescue instrument for identifying, monitoring, and guiding the application of brain therapies to patients with evolving brain injuries, comprises input means ( 101 - 103 ) for acquiring a multiple number of signals each indicative of a different biochemical or biophysical parameter of a patient, computing means ( 104 - 107 ) to continuously sample each of the acquired signals and display to a user on a monitor ( 109 ) at least some of the parameters, the displayed parameters being selected by system software embodying expert analytical rules as the most significant parameters, or as parameters having values indicative, or predictive at any time of actual, or potential future deterioration of the brain state of the patient.

FIELD OF INVENTION

[0001] This invention relates particularly to data evaluation equipmentand procedures for the monitoring and management of brain injuries inmammals.

BACKGROUND

[0002] The brain can be compromised by a number of adverse influencesduring all stages of life including perinatal asphyxial andhypoperfusion insults, strokes, traumatic brain injuries, cardiacarrest, cardiac bypass surgery, poisoning, and subarachnoidhaemorrhages. Considerable variation occurs in the degree anddistribution of neuronal loss depending on the type and severity of theinjury to the brain.

[0003] Injury results in two recognised phases of neuronal loss (seeFIG. 16 of the accompanying figures): primary neuronal death isassociated with the insult itself, and delayed neuronal death occursduring a secondary phase some hours later, when a complex pathologicalcascade of events leading to neuronal death follows the initial injury.A transient insult, such as hypoperfusion, can cause brain cells to diein two phases. The primary phase extends throughout the insult and theearly regeneration/reperfusion period. Processes contributing to thisprimary phase include intracellular Na⁺ and Ca²⁺ accumulation, cytotoxicedema, membrane damage, free radicals, and excitotoxicity. However, manyneurons do not necessarily die during the primary phase but cytotoxicmechanisms are triggered that lead to a further or delayed death ofneurons some hours later. The mechanisms involved in delayed neuronaldeath are thought to include excitoxicity, seizures, apoptosis, andmicroglial activation.

[0004] Recent studies suggest that it is possible to interfere withthese mechanisms and thereby rescue susceptible neurons. Biophysicalmeasures of the pathophysiologic processes preceding and during thephases of neuronal death are likely to prove useful for identifyingthose patients who may benefit from neuronal rescue therapies. Severalclinically relevant factors such as pre-existing injuries, hypotensionor metabolic status may sensitise and alter the response of the brain toinjury. Several biophysical parameters recorded during and after aninsult are generally needed to reliably discriminate the present phaseof injury and periods of cytotoxic activity.

[0005] The monitoring of patients with brain injuries whether caused byexternally induced trauma such as birth or accident or by circulatoryproblems or poisoning has hitherto relied upon clinical signs but thesemay not be observable until a time at which the damage may have becomeirreversible. Neurological examination is of limited value (inparticular for those on life support apparatus) for predicting outcomeand determining the phase of injury. Similarly, use of imagingtechniques such as MRI and CT are not practical for monitoring evolvinginjuries in these patients.

SUMMARY OF INVENTION

[0006] The invention provides an intelligent monitoring instrument,termed a brain rescue instrument or monitor, and method, for monitoring,identifying and guiding the application of brain therapies to patients,with evolving brain injuries, and generally for assisting with themanagement and treatment of brain injury in a mammalian patient.

[0007] In broad terms in one aspect the invention comprises anintelligent brain rescue instrument for identifying, monitoring, andguiding the application of brain therapies to patients with evolvingbrain injuries, comprising:

[0008] input means for acquiring a multiple number of signals eachindicative of a different biochemical or biophysical parameter of apatient, and

[0009] computing means configured to continuously sample and processeach of the acquired signals and display to a user on a monitor at leastsome of the parameters, the displayed parameters being selected bysystem software embodying expert analytical rules as the mostsignificant parameters or as parameters having values indicative orpredictive at any time of actual or potential future deterioration ofthe brain state of the patient.

[0010] In broad terms in another aspect the invention comprises anintelligent brain rescue instrument for identifying, monitoring, andguiding the application of brain therapies to patients with evolvingbrain injuries, comprising:

[0011] I) input means for acquiring a set of a multiple number ofsignals each indicative of a different biochemical or biophysicalparameter of the patient, said set of signals being selected from:

[0012] (a) an EEG signal;

[0013] (b) an ECG signal;

[0014] (c) a signal indicative of brain tissue impedance of the patient;

[0015] (d) signal or signals indicative of the temperature of thepatient;

[0016] (e) signals indicative of the arterial blood pressure and/orarterial oxygen saturation, of the patient;

[0017] (f) a signal indicative of intracranial pressure;

[0018] (g) a signal or signals indicative of any of cerebral blood flow,cerebral blood volume, cerebral oxygenation, or cerebral metabolitemeasures;

[0019] (h) a signal or signals indicative of systemic glucoseconcentration and/or central glucose concentration;

[0020] (i) a signal or signals indicative of systemic lactateconcentration and/or central lactate concentration;

[0021] (j) a signal indicative of cerebrovascular status;

[0022] (k) a signal indicative of cerebral cytochrome levels;

[0023] (l) a signal indicative of the patient's heart rate;

[0024] (m) a signal indicative of central cytotoxic activity;

[0025] (n) a signal or signals indicative of movement or muscleactivity;

[0026] (o) a signal or signals indicative of any other biochemical orbiophysical parameter useful as indicative of the current or aspredictive of the future brain state of the patient; and

[0027] II) computing means configured to:

[0028] (a) continuously sample and process each of the acquired signals;and

[0029] (b) display to a user on a monitor information a selected subsetof the acquired parameters, said selected subset of parameters which isdisplayed being selected either by system software embodying expertanalytical rules as the most significant parameters or as parametershaving values indicative or predictive at any time of actual orpotential deterioration of the brain state of the patient, with saidparameters being displayed against a scale or scales or in a way whichhighlights to a clinician any variations of the parameters indicative orpredictive of the deterioration of the brain state of the patient, oralternatively being override selected at any time by the user.

[0030] In broad terms in a further aspect the invention comprises amethod for identifying, monitoring, and guiding the application of braintherapies to patients with evolving brain injuries, comprising acquiringa multiple number of signals each indicative of a different biochemicalor biophysical parameter of a patient, and via computing meanscontinuously sampling each of the acquired signals and displaying to auser on a monitor at least some of the parameters, the displayedparameters being selected by system software embodying expert analyticalrules as parameters having values indicative or predictive at any timeof actual or potential future deterioration of the brain state of thepatient, with said parameters being displayed against a scale or scalesor in a way which highlights to a clinician variations of the parametersindicative or predictive of deterioration in the brain state of thepatient.

[0031] The brain rescue instrument monitors at least some of thepathophysiologic and temporal events surrounding encephalopathies—whichevents are predictive of pathological neuronal death or can influencethe degree of secondary injury. This information is a prerequisite todeciding whether or not intervention with neuronal rescue therapy isindicated. The invention enables a better detection procedure forpredicting the secondary loss of brain cells, so that steps to alleviatesecondary injury may be taken as soon as possible and even before theappearance of clinical signs, to achieve increased survival and betterlong-term prospects of patients.

BRIEF DESCRIPTION OF THE FIGURES

[0032] The invention will be further described with reference to theaccompanying drawings in which:

[0033]FIG. 1 is a view of a preferred form trolley mounted brain rescuemonitor of the invention,

[0034]FIG. 2 shows an overview of the hardware and software systems ofthe preferred from brain rescue monitor,

[0035]FIGS. 3 and 4 show screen displays of the preferred form brainrescue monitor,

[0036]FIG. 5 shows preferred EEG electrode placement for use with thepreferred form brain rescue monitor.

[0037] FIGS. 6(a) to (e) are graphs of a series of cortical temperaturetreatment profiles following hypoxia,

[0038]FIG. 7(a) to (e) graphically show examples of effects of long termtemperature trends on outcome.

[0039]FIG. 8 graphically shows cytotoxic activity as sensed bymicrodialysis, against time,

[0040]FIG. 9 graphically shows examples of the T/QRS ratio from an ECGafter injury,

[0041]FIG. 10(a) and (b) graphically show seizure and spike activityafter injury, overtime,

[0042] FIGS. 11(a)-(c) illustrate relationships between EEG parametersand outcome,

[0043] FIGS. 12(a) and (b) are tables which correlate blood pressure andother factors, vs neuronal outcome,

[0044]FIG. 13 graphically relates the duration of ischemia to neuronalloss in specific areas of the brain,

[0045]FIG. 14 graphically illustrates cytotoxic activity as levels ofcitrulline (a marker of nitric oxide activity) and as cortical impedance(CT) vs time,

[0046]FIG. 15 graphically shows by example the effect of growth factor(rhIGF-1) rescue therapy on pathophysiology,

[0047]FIG. 16 diagramatically shows the phases of brain injury.

[0048] FIGS. 17(a) to (c) graphically show an example of the effect ofMK801, a NMDA antagonist, on seizures and outcome,

[0049]FIG. 18 shows a further set of curves relating cerebral impedance(CI), perfusion (tHb), cytochrome oxidase (Cyt02), and EEG intensity, totime,

[0050]FIG. 19 is a table which correlates cortical neuronal loss versusperfusion,

[0051]FIG. 20 graphically shows the time course of global cerebral bloodflow following hypoxic-ischemic injury (p<0.05),

[0052] FIGS. 21(a)-(d) graphically show the time course of changes inparietal cortex extracellular lactate, glucose, ECoG intensity andcortical impedance that occurs during and for 3 days following a 30minute hypoxic-ischemic injury (p<0.05)

DETAILED DESCRIPTION OF PREFERRED FORM

[0053] The preferred form brain rescue monitor samples, processes, datareduces, stores and evaluates various biochemical and biophysicalparameters of relevance to the management of an individual patient withbrain injury. The system comprises system software embodying expertanalytical rules for managing signal handling and for signal analysis.The system displays information on some of those which are monitored,which are those most significant for the patient type and/or injurytype, against a scale in a way which highlights any variations in theparameters indicative or predictive of deterioration in the brain stateof the patient. The system monitors other input signals in background,and provides an indication to the user if any of those backgroundsignals or parameters varies to indicate a deterioration of the brainstate of the patient. The indication may be by a pop up window whichdisplays information concerning the previously background parameter, orother warning to the user. The collection of all of the information maybe used by a physician in the monitoring and management of braininjuries and guiding the application of brain rescue therapies.

[0054] The system hardware of the preferred form brain rescue monitorcomprises an embedded microprocessor with associated data acquisitionstages to which electrodes or sensors connected to the patient, otherinstrumentation, or any other signal sources are connected. A screendisplays information on selected monitored parameters.

[0055] Referring to FIG. 1, the preferred form brain rescue monitor unit1 is carried on a rolling stand 2 having an internal pneumatic springwhich allows the unit 1 to be adjusted at to different heights at apatient's bedside, for example. A battery 3 is, in the preferred form,mounted to the base of the stand as shown, either as the primary powersource for the unit or as a back up to mains power to ensure reliableoperation. In alternative forms the unit may be wall mounted, otherwisebedside mounted, or even formed as a smaller unit which is attached tothe patient's head or body for example.

[0056]FIG. 2 shows the major components of the preferred form system.The preferred form system has input channels and data acquisitionelectronics for an EEG signal, an ECG signal, a cortical impedancesignal, cerebral and core temperature signals, arterial blood pressureand arterial oxygen saturation signals, an intracranial pressure signal,cerebral blood flow, cerebral blood volume, cerebral oxygenation andcerebral metabolic signals, systemic glucose concentration and centralglucose concentration signals, a cerebrovascular status signal, centralcytochrome levels, heart rate, central cytotoxic activity, patientmovement or muscle activity. A number of these input signals such asEEG, ECG, cortical impedance, intracranial pressure, near infraredspectroscopy, microdialysis analyses and temperature sensors areobtained as is known in the art via sensors attached to or within thepatient's head. A number of parameters can be sensed through EEGelectrodes such as the EEG itself, seizure and spike activity, andcerebral impedance, and an ECG. In some cases, data for one inputparameter can be extracted from input data on one or a number of otherinput parameters, eg heart rate can be extracted from blood pressure,ECG, and pulse oximetery. In general, sensors used to obtain inputsignals may include fiberoptic leads, tubes, biosensors, pressuretransducers, dialysis probes, flow transducers, thermistors and movementsensors for example. In FIG. 2, a patient's cranium is indicated at 100,and a set of EEG leads are shown at 101 as an example of an input signalsource. Leads 102 and 103 also attached to the patient's scalp indicateother input signal sources.

[0057] The input signals are filtered as necessary, amplified andanalogue-to-digital converted where necessary, and optionallymultiplexed together, as indicated by block 104, and passed to databuffer 105. Other input parameter data from other instruments forexample or other data sources may optionally also be input to databuffer 105.

[0058] The digitised input signals data may also be compressed andstored. Data compression may involve averaging or time-to-frequencydomain conversion. Standard computer-compatible data storage deviceswith a standard system for file naming and configuration are utilised.The system is capable of carrying out data reduction, featureextraction, or compression, of incoming signals of a variety of types.For example, EEG spectra and ECG waveform data are averaged. Inparticular, conversion of an EEG, for example, from the time domain tothe frequency domain prior to storage can result in a substantialreduction of data, as does recording of its mean intensity. Datareduction is a common consequence of median and/or other forms offiltering.

[0059] At block 107 the expert system software embodying expertanalytical rules represented by block 108 is applied to the current andthe stored data for the patient being monitored. The expert system rulesare developed from accumulated experimental and clinical experience, asdescribed subsequently. The system continuously samples and analyseseach of the input channels, at a rate appropriate to the input channel.The expert software system may be considered as a number of brain rescuetask instruments indicating various parameters from the input data. Ineither case the software system is configured to display at least someof the parameters being monitored, either selected by the expertsoftware system as the most appropriate to display to the clinician forthe particular patient case, or a combination of parameters which isoverride selected by the clinician. The parameters which are normallydisplayed in the foreground for the particular patient case are thosethat together increase the ability to predict the outcome, or identifythe phase of injury, or guide the selection and/or the application of atherapy to the patient. The software continues to monitor thenon-displayed parameters in background and if any of these is consideredby the expert software system to be such as to indicate a deteriorationof the brain state of the patient, the software causes the previouslybackground parameters) to be displayed, by a pop up window showing theparameter value graphically for example, or causes a warning to be givento the user in some other way via an appearing icon or similar,optionally accompanied by an audible alarm if appropriate.

[0060]FIG. 2 also comprises a dataflow diagram and illustrates thatdigital signals are fed continuously into input data buffer 105,subsequently the bulk of the data flow is through the signal analyticalmodules 106, and then through the expert brain rescue task modules 107,and to the display, or data storage device(s). The signal analyticalmodules perform artefact rejection, signal processing and analysis, anddata reduction. The expert brain rescue task modules then selectinformation from these modules and process the information to aidspecific brain rescue tasks. The brain rescue task modules select thepertinent biophysical measures to display and set the normal andpathological display ranges and data display modes and display scales.

[0061] For the foreground parameters the display normally shows the mostrecent period of data collection, and highlighted on the display, foreach biochemical-or biophysical parameter, are any points where there isat least a suspicion of pathophysiologic levels, or the optimal rangefor the biochemical or biophysical parameter that can influence outcome.For example, a line or series of points graphically illustrating amonitored parameter can be displayed in green where the correspondingparameter is clearly within a normal range, or in yellow, and then redfor values that the expert system predicts to be unsafe or dangerous. Amonochrome display may use brighter or flashing lines or points. Displayscales may be non-linear particularly in the display of spectra or wherelogarithmic displays are already accepted. The display may also benon-linear in the time axis if this can be portrayed without riskingconfusion. Alternatively different windows on a screen may displayshort-term events or long-term events respectively.

[0062] User interaction with and control of the system in the preferredform system is via a touch sensitive screen but may alternatively be viaa touch panel or keypad 109 (see FIG. 2), on the front face of thepreferred form instrument for example, a keyboard and/or a mouse, aseparate hand held infra-red unit, or other convenient form of inputdevice.

[0063] The unit may include a printer port 113 or a built-in printer, ora network interface.

[0064] Both short-term events (of the order of 4 seconds) and long-termevents (of the order of hours or days) are resolved, evaluated, anddisplayed. The sampling rates used are capable of resolving brief eventsand also of separating a real, brief event from an artefactual single orseries of false values, and the unit is capable of storing and recallingof any or all records over a period of for example 3 days or more. Suchartefacts and interference from the input parameters may be minimisedvia one or more hardware or software filters, and/or via expert rules inthe software applied at the signal processing stage indicated by block106 capable of rejecting events not in accordance with the time scale ofthe signal being recorded. For example, EEG recordings become unreliablewith increased electrode impedance and/or amplifier saturation and/orpresence of movement artefact, and one sign of movement artefact israpid fluctuations in the shape of the waveform. A preferred softwarefilter is a median filter which tends to reject extreme values such asthose resulting from a switching transient coupled to the body.

[0065] The system is so far as possible is capable of assessing theeffectiveness of sensor connections and informing the user of any signalchannels that appear to be incorrect. The system monitors each signalline in order to confirm that each channel continues to provide reliableresults because (for example) attached electrodes can be detached orlose effectiveness in other ways. In the event of a problem thecorresponding data is disregarded and a warning message is generated.FIG. 5 shows a display screen of the preferred form brain rescue monitorwhich illustrates the preferred EEG electrode placement, and which mayalso indicate to the user any detached or ineffective electrode. Thesystem will also calibrate itself, as far as possible, so that readingsare quantitative. This means that they have a greater reliability andsignificance to an expert system.

[0066]FIG. 3 shows a screen display of the preferred form brain rescuemonitor. Information relevant to specific brain rescue tasks or for themonitoring or management of brain injuries is displayed on the screen(see text and observational data). The information to be displayed isselected by the user via the menus such as the brain rescue task menudisplayed along the bottom left of the screen. In this example timetrend information describing pathophysiologic, cytotoxic and physiologicprocesses are displayed graphically in the upper left region. Incomingsignals are monitored in the upper right region and current patientstatus information is displayed in the panel on the right. The user mayalso mark events, access the help information or alter the settings ofthe machine via the menus in the lower right corner of the screen. Theuser also can alter the information displayed within specific regions byaccessing the associated menus.

[0067]FIG. 4 shows another screen display of the preferred form brainrescue monitor for the evaluation and analysis of historical and/or dataremotely recorded by the brain rescue monitor. The user can select theinformation to be displayed, zoom, scroll, take measurements, filter,process or print or extract information as required via the menus.

[0068] More generally in relation to system alarms, the expert systemmay give a warning to the user when an alarm limit for any parameter isexceeded, by an alarm tone graded according to severity, a visual alarmmessage colour coded according to severity or by flashing a visual alarmmessage for a particular parameter, for example. Alarms can beindefinitely suspended for 1, 2 or 3 minutes, after which the alarm willautomatically reactivate. In the preferred form unit to prevent unwantedalarms, the parameters which will trigger an alarm may be entered by theclinician. Alarms may be graded and prioritised for example as redalarms to indicate a critical situation occurring; yellow alarms toalert clinicians when alarm limits are exceeded; and technical alarmswhich are triggered by signal quality noise and problems, and equipmentmalfunction.

[0069] Optionally the system may make available expert advice having aninbuilt ability to predict outcome and/or to identify the pathologicalprocesses taking place through an advisor/help system. Some of the rulesby means of which this can be set up are evident from the followingobservational evidence, and an expert system for indicating anappropriate response may be based on a set of rules, and/or on fuzzylogic (such as numerical weighting of observations), and/or neuralnetworks, and/or analytical models, a combination of those, or thoseplus additional computational abilities. The system may also makeavailable representative examples of pathophysiologic reactions whichcan be called up by a user contemplating the case under study.Representative case studies may assist users to interpret findings, andmay assist expert system in making its findings.

[0070] The software system applies an expert system of rules or expertanalytical models to the signals so that the stage of evolution of headinjury can be identified; the trends in the evolution of the case arerecognised; cytotoxic processes can be identified; a likely outcome canbe determined; and therapy can be recommended, particularly if sometreatable and dangerous condition such as epileptiform activity (whichmay not result in motor activity) is identified.

[0071] The parameters which can be usefully monitored in any case may bededucted from the observational evidence disclosed below but specificexamples of brain rescue tasks and the corresponding pathophysiologic,cytotoxic and physiologic responses that can be usefully monitoredinclude:

[0072] Patient selection for rescue therapy: eg selection of infants whohave suffered an asphyxial episode for neuronal rescue therapy. Thebiophysical signals monitored includes measures of some of the followingpathophysiologic and cytotoxic processes:

[0073] Comprised cortical electrical activity eg loss of EEG intensityand/or amplitude and/or frequency.

[0074] Presence of cardiovascular injury eg presence of hypotensionand/or changes within the ST segment of the electrocardiogram.

[0075] Presence of cerebral mitochondrial dysfunction or alteredmetabolism: eg increased cerebral lactate production and/or reducedcerebral oxygen consumption.

[0076] Altered cerebrovascular tone eg increased cerebral blood flowand/or blood volume or decreased cerebral blood flow and/or bloodvolume.

[0077] Patient rejection criteria can include some of the following:

[0078] Presence of normal EEG activity eg EEG intensity and/or amplitudeand/or frequency within normal range.

[0079] Evidence of persistent cytotoxic edema eg persistently elevatedbrain tissue impedance.

[0080] Evidence of brain death eg persistent loss of brain blood flow.

[0081] Postasphyxial seizure detection and management: eg foridentifying and guiding therapy of those suffering from postasphyxialseizures. Therapy may be either anticonvulsant or antiexcitotoxicagents. The biophysical signals monitored includes measures of some ofthe following pathophysiologic and cytotoxic processes:

[0082] Cortical seizure activity eg presence of seizure activity on theEEG signal.

[0083] Level of background EEG activity eg EEG intensity and/oramplitude and/or frequency.

[0084] Spatial distribution of some of above EEG parameters eg derivedfrom EEG signals recorded at multiple sites.

[0085] Cytotoxic edema eg presence of increased brain tissue impedance.

[0086] Excitotoxic activity eg presence of increased glutamate in thebrain cerebrospinal fluid and/or extracellular fluid.

[0087] Compromised cerebral metabolism eg reduced cerebral oxygenconsumption and/or increased cerebral lactate production and/or lactatelevels in cerebrospinal fluid.

[0088] Presence of hyperaemia eg increased cerebral blood flow.

[0089] Synchronous increases in blood pressure and/or heart rate, and/orblood flow and/or muscle activity.

[0090] Increases in core and/or cerebral temperature.

[0091] Monitoring of electrophysiologic signal validity: Signals to bemonitored may include some of the following:

[0092] Range of electrode impedance.

[0093] Level of mains hum.

[0094] Presence of amplifier clipping.

[0095] Presence of input amplifier saturation.

[0096] Level of movement artefact.

[0097] Application of therapeutic hypothermia: The biophysical signalsmonitored includes measures of some of the following physiologic andpathophysiologic processes:

[0098] Core, cerebral and related temperatures:

[0099] These temperatures are referred against an optimal temperaturerange that depends on the protocol for example: term infants may becooled to a core temperature of about 35° C. and adults 33° C.

[0100] Duration of cooling for example about 12-72 h post injury.

[0101] Rate of progressive rewarming eg about 1° C. per hour.

[0102] Heat transfer device(s) temperature status and heat flux(es).

[0103] Metabolic or cardiovascular compromise eg systemic lactate levelsand/or hypotension.

[0104] Pathophysiologic or cytotoxic processes influenced by thehypothermia such as cytotoxia edema, vasogenic edema, excitotoxicity, orcerebral lactate production.

[0105] Maintenance of optimal status to minimise delayed neoronalinjury: The biophysical signals monitored includes measures of thelevels of some of the following physiologic and pathophysiologicprocesses:

[0106] Glucose levels eg serum levels and/or cerebrospinal fluid levels.

[0107] Core and/or cerebral temperature.

[0108] Blood pressure eg above a minimal hypotensive) level.

[0109] Cerebral oxygenation eg measured by near infrared spectroscopy.

[0110] Cerebral perfusion eg measured by ultrasonic methods.

[0111] Intracranial pressure eg measured by intracerebral pressuresensors.

[0112] Presence of seizures eg detected on the EEG signals.

[0113] Observational Evidence

[0114] The following comprises observations for particular biophysicalparameters. By appropriate weighing of each parameter an expert systemfor many cases can be produced capable of correctly assessing the likelypatient outcome, of indicating the need for specific treatment (such asanti-seizure treatment, seizures seem to immediately precede secondaryneuronal death), and of indicating the progress. The brain rescuemonitor enables the amount of data assessed to exceed that which anindividual clinician can adequately comprehend.

[0115] Cerebral electrical activity—EEG: Referring to FIGS. 10, 11, 12and 18, prolonged depression of EEG activity after injury is predictiveof neuronal loss. Hypothermia or rescue therapies should be initiated inthe depression phase, and a depressed EEG is associated with increasedsusceptibility to further injuries. Recovery of normal activity isassociated with good outcome.

[0116] Patient seizure activity (detected via EEG electrodes): Referringto FIG. 10 and FIGS. 8, 14 and 18 linking EEG activity to impedance,seizure activity after injury is predictive of neuronal loss, prolongedcortical seizure activity is predictive of cortical infarction, seizureactivity and/or rise in impedance is associated with excitotoxicity (seelater for details of impedance), seizure activity develops concomitantlywith the secondary rise in impedance, seizure activity occurring withlowering of frequency predicts neuronal loss, synchronous increases EMGactivity or rises in blood pressure or cerebral impedance are associatedwith severe seizures, Seizure activity is suppressed during effectivetherapy with antiexcitotoxic or anticonvulsant (FIG. 17) agents, and EEGdepression before the onset of spike and/or seizure activity isassociated with poor outcome (FIGS. 11, 12(b) and 18). Intermittentseizure activity superimposed on normal EEG activity is associated withstriatal injury (FIG. 10).

[0117] Patient spike activity (detected via EEG electrodes): Referringto FIGS. 10 and 17, spike activity (bursts of rapid waves) is predictiveof neuronal loss, spike activity often precedes seizure activity, andspike activity after depressed EEG and/or rise in cerebral impedance ispredictive of neuronal loss. Spike activity superimposed on normal EEGactivity is associated with striatal injury, and it is useful for thesystem to raise an immediate alarm if spike injury is detected (FIG.10). The effect of administering MK801 is illustrated in FIG. 17; wherethe cortical impedance trace shows a much reduced rise.

[0118] Cerebral impedance (detected via EEG electrodes): Referring toFIGS. 8, 14, 15 and 18, rising impedance is associated with tissueenergy failure, cytotoxic edema, rising impedance and EEG depression isassociated with tissue energy failure, rising impedance and ischemia isassociated with tissue energy failure, a reversible increase inimpedance predicts delayed damage, and an acute rise in impedancepredicts increased susceptibility to further injuries. (Gangliosidetherapy can be used to counteract against increased susceptibility.)Irreversible acute risk in impedance predicts infarction, increasedimpedance is associated with accumulation of excitotoxins (FIGS. 8, 14,17), prolonged secondary rise in impedance is associated with infarctionand edema, gradually rising impedance and seizure activity is associatedwith the development of an infarct, prolonged large rise in impedanceand loss of electrical activity is associated with brain death, a risein impedance associated with the secondary phase of injury is associatedwith neuronal loss, falling impedance after a prolonged rise isassociated with infarction, falling impedance and resolution of seizureactivity or loss of EEG activity is associated with infarction, regionalchanges in impedance are associated with the location of injury, andcerebral impedance is influenced by temperature. Repetitive increases inimpedance are associated with striatal injury. One example ofalleviation of the signs of cerebral impedance changes is given in FIG.15, where varying amounts of the growth factor rhIGF-1 (or vehiclealone) were given to ovine foetuses at about two hours after ischemia.There are a number of other possible treatments.

[0119] Cerebral haemodynamic status: Referring to FIGS. 18 and 20, lossof cerebral oxygenation is associated with injury: The duration ofprimary hyperaemia (increased blood flow and/or blood volume) ispredictive of poor outcome, the onset time of secondary hyperaemia ispredictive of severity, secondary hyperaemia precedes edema and/orseizures, and hyperaemia increases during seizures and/or edema.Episodes of venous desaturation are associated with poor outcome.

[0120] Cerebrovascular status: Referring to FIGS. 18, 19 and 20,impaired autoregulation is associated with poor outcome, and regionalchanges are predictive of outcome.

[0121] Cerebral blood flow: Referring to FIGS. 19 and 20, impairedcerebral blood flow is associated with injury, and increases in cerebralblood flow are associated with cerebral seizure activity and delayedinjury. The degree of hypoperfusion during the immediate reperfusionperiod and an inverse relationship with the magnitude of delayedhyperperfusion are predictive of the severity of neuronal loss (FIG.12b). Reactive hyperaemia occurs during the delayed phase of cell deathafter injury and may protect marginally viable tissue (FIGS. 18 and 20).

[0122] Cytotoxic activity: Referring to FIGS. 8 and 14, a rise inextracellular citrulline, a by product of nitric oxide, is associatedwith delayed injury. Excitotoxins, such as glutamate, accumulate duringthe later phases of injury (FIGS. 8 and 17). Increased levels ofcytotoxins are associated with poor outcome.

[0123] Lactate status: Referring to FIG. 21, Increased production oflactate, a marker for mitochondrial damage, is associated with the earlyphase of injury. Elevation in lactate levels are associated with thedelayed phase of injury.

[0124] Glucose status: Referring to FIG. 21, an elevation in glucose isassociated with the delayed phase of injury. Both hypoglycaemia andhyperglycaemia can worsen brain injury.

[0125] Spatial distribution: Referring to FIG. 13, spatial distributionsof cerebral pathophysiologic processes are monitored because spatialchanges are associated with the location of pathophysiologic processeseg changes in EEG can be used to localise changes.

[0126] ECG: Referring to FIGS. 9 and 12, the occurrence of ST changesafter asphyxia is predictive of neuronal loss, T wave changes afterasphyxia is predictive of neuronal loss, and acute changes in T/QRSratio are associated with cerebral injury.

[0127] Temperature: Referring to FIGS. 6 and 7, preferably at leastcore, tympanic and scalp temperature are monitored. Hyperthermiaexacerbates injury until cerebral function has fully recovered, whileprolonged hypothermia suppresses neuronal death, scalp temperatureinfluences cortical damage, and core temperature influences damage indeeper brain structures.

[0128] Arterial blood pressure is monitored, because hypertensionincreases the risk of injury: Referring to FIG. 12 cerebral perfusionpressure is monitored because low cerebral perfusion pressure increasesrisk of injury, secondary rise in impedance precedes brain swelling, anddevelopment of hyperaemia then rising impedance predicts brain swelling(FIG. 18).

[0129] The foregoing describes the invention including a preferred formthereof. Alterations and modifications as will be obvious to thoseskilled in the art are incorporated in the scope of the invention, asdefined in the following claims.

1. An intelligent brain rescue instrument for identifying, monitoring,and guiding the application of brain therapies to patients with evolvingbrain injuries, comprising: I) input means for acquiring a set of amultiple number of signals each indicative of a different biochemical orbiophysical parameter of the patient, said set of signals including amultiple number of signals selected from: (a) an EEG signal; (b) an ECGsignal; (c) a signal indicative of brain tissue impedance of thepatient; (d) signal or signals indicative of the temperature of thepatient; (e) signals indicative of the arterial blood pressure and/orarterial oxygen saturation, of the patient; (f) a signal indicative ofintracranial pressure; (g) a signal or signals indicative of any ofcerebral blood flow, cerebral blood volume, cerebral oxygenation, orcerebral metabolite measures; (h) a signal or signals indicative ofsystemic glucose concentration and/or central glucose concentration; (i)a signal or signals indicative of systemic lactate concentration and/orcentral lactate concentration; (j) a signal indicative ofcerebrovascular status; (k) a signal indicative of cerebral cytochromelevels; (l) a signal indicative of the patient's heart rate; (m) asignal indicative of central cytotoxic activity; (n) a signal or signalsindicative of movement or muscle activity; (o) a signal or signalsindicative of any other biochemical or biophysical parameter useful asindicative of the current or as predictive of the future brain state ofthe patient; and II) computing means configured to continuously sampleand process each of the acquired signals, and display to a user on amonitor information a selected subset of the acquired parameters, saidselected subset of parameters which is displayed being selected eitherby system software, including signal analysis modules arranged toperform initial signal processing and analysis and brain rescue taskmodules arranged to process data from the signal analysis modules andembodying expert analytical rules, as parameters having valuesindicative or predictive at any time of actual or potential futuredeterioration of the brain state of the patient, with said parametersbeing displayed against a scale or scales or in a way which highlightsto a clinician any variations of the parameters indicative or predictiveof the deterioration of the brain state of the patient to enableidentification, monitoring, and guiding of the application of braintherapies to a patient with an evolving brain injury, or alternativelybeing override selected at any time by the user.
 2. An intelligent brainrescue instrument according to claim 1, wherein the computing means isconfigured to store data collected over several days in relation to atleast some of the selected parameters and the system software embodyingexpert analytical rules is arranged to identify variations in saidparameters occurring over a period of a number of hours or days as wellas short term events occurring over a number seconds.
 3. An intelligentbrain rescue instrument according to either one of claims 1 and 2,including hardware and/or software filters to minimise noise and/orartefacts or interference in the input parameter signals.
 4. Anintelligent brain rescue instrument according to any one of claims 1 to3 wherein said expert system software is configured to identify andignore artefacts and interference in the input parameter signals.
 5. Anintelligent brain rescue instrument according to any one of claims 1 to4 including a software based advisor or help system arranged to provideexpert advice based on rules or models in the software to assist aclinician.
 6. An intelligent brain rescue instrument according to anyone of claims 1 to 5 including means for data reduction and storage ofhistoric parameter information.
 7. An intelligent brain rescueinstrument according to any one of claims 1 to 6 wherein the systemsoftware is arranged to identify and indicate fault conditions indicatedby at least some of the input signals.
 8. A method for identifying,monitoring, and guiding the application of brain therapies to patientswith evolving brain injuries, comprising: I) acquiring a set of signalseach indicative of a different biochemical or biophysical parameter ofthe patient, said set including a multiple number of signals selectedfrom: (a) an EEG signal; (b) an ECG signal; (c) a signal indicative ofbrain tissue impedance of the patient; (d) signal or signals indicativeof the temperature of the patient; (e) signals indicative of thearterial blood pressure and/or arterial oxygen saturation, of thepatient; (f) a signal indicative of intracranial pressure; (g) a signalor signals indicative of any of cerebral blood flow, cerebral bloodvolume, cerebral oxygenation, or cerebral metabolite measures; (h) asignal or signals indicative of systemic glucose concentration and/orcentral glucose concentration; (i) a signal or signals indicative ofsystemic lactate concentration and/or central lactate concentration; (j)a signal indicative of cerebrovascular status; (k) a signal indicativeof cerebral cytochrome levels; (l) a signal indicative of the patient'sheart rate; (m) a signal indicative of cytotoxic activity; (n) a signalor signals indicative of movement or muscle activity; (o) a signal orsignals indicative of any other biochemical or biophysical parameteruseful as indicative of the current or as predictive of the future brainstate of the patient; and II) via computing means: (a) continuouslysampling each of the acquired signals; and (b) displaying to a user on amonitor information on a selected subset of the acquired parameters,said selected subset of parameters which is displayed being selected bysystem software, including signal analysis modules arranged to performinitial signal processing and analysis and brain rescue task modulesarranged to process data from the signal analysis modules and embodyingexpert analytical rules, as parameters having values indicative orpredictive at any time of actual or potential future deterioration ofthe brain state of the patient, with said parameters being displayedagainst a scale or scales or in a way which highlights to a clinicianany variations of the parameters indicative or predictive of thedeterioration of the brain state of the patient to enableidentification, monitoring, and guiding of the application of braintherapies to a patient with an evolving brain injury.
 9. A methodaccording to claim 8, wherein said monitoring is carried outcontinuously over a period of at least twelve hours.